Pertinent Art. The claimed group of inventions relates to medicine, and specifically to medicinal preparations and compositions used for the prevention and treatment of bone resorption, namely, osteoporosis, Paget's disease, and pathological fractures in cancer patients, as well as for the prevention of osteoporosis in menopause.
Prior Art. When introduced into warm-blooded organisms, sodium alendronate exhibits osteoselectivity and interacts with bone tissue as a specific inhibitor of osteoclast-mediated bone resorption. As a synthetic analogue of pyrophosphate, sodium alendronate specifically binds to hydroxyapatite of bones, thus preventing resorption of bone tissue.
At the same time, sodium alendronate as a medicinal preparation has significant shortcomings, for instance, extremely low bioavailability (under 1%) when taken orally; it often causes complications associated with irritation and mucosal ulceration of the gastrointestinal tract (GIT), and hence, cannot be prescribed for a substantial group of patients suffering from diseases of the GIT.
It is generally accepted that the entrance of biphosphonates into systemic circulation, even in the case of intravenous injection, is not a matter of principle in the treatment of osteoporosis or other diseases with bone resorption. The main thing is the delivery, distribution and exposure of biphosphonates on the surface of porous bones.
It is well known that biophosphonates can be absorbed when applied on the skin. Ferrini P. G. et al. proposed methods for optimization of penetration of salts of diphosphone acids through the skin (EP 0407344, published Feb. 27, 1991). The method's shortcoming is the fact that biophosphonates in proposed formulations have a hard time penetrating subcutaneous fat and are rapidly eliminated from the “depot.” Furthermore, in order to optimize transdermal transport, additional elements are used that can cause skin irritation or allergic reactions.
Proposed is a method for the local application of sodium alendronate by the delivery of soft capsules or cream in vaginal suppositories through vaginal mucosa (U.S. Pat. No. 6,905,701, published Jun. 14, 2005). However, this method has significant shortcomings caused by the irritation effect of alendroate on mucosa and by limitations on the use of the preparation related to a patient's gender. Known from prior art is the local use of sodium alendronate for the prevention and treatment of bone desorption of various etiology, wherein the delivery of the active ingredient is done using ionophoresis (U.S. Pat. No. 6,008,206, published Dec. 28, 1999). The shortcoming of this proposal is the fact that the delivery of sodium alendronate by ionophoresis makes it possible to obtain insignificant concentrations of the preparation at the point of entry and requires the use of special medical equipment.
The closest to the proposed invention as far as the technical essence is concerned is a pharmaceutical composition for the treatment of osteoarthritis and osteoporosis of varying etiology, comprising sodium alendronate, white vaseline, salicyl alcohol, white bees wax, glycerin, liquid paraffin, sodium lourilsulphate and water, as well as a method for the local application of sodium alendronate, that includes selective delivery of the preparation to places of increased resorption of bone tissue (U.S. Pat. No. 5,958,908, published Sep. 28, 1999).
The shortcomings of this composition and method of application is the impossibility of ensuring the necessary concentration of sodium alendronate in tissues and bones directly in the area of localization of the pathological process due to the low penetrability of the active substance in the base proposed by the authors.
Disclosure of Invention. The technical result of the claimed group of inventions is that the proposed contents of the composition for transdermal delivery makes it possible to ensure a sufficiently high concentration of sodium alendronate in tissues and bones directly in the area that the preparation is applied to the skin, without using additional medical equipment or techniques (e.g., ionophoresis, electrophoresis, massage infriction, and injection of the preparation).
The objective of the proposed group of inventions, connected by a single inventive idea and related by a single inventive concept, is the creation of a pharmaceutical composition of sodium alendronate in a gel dosage form and a method for using it for transdermal application. Under the method, sodium alendronate or other biphosphonates are in liposomes which substantially improve the bioavailability of sodium alendronate and create conditions for long-term local retention of therapeutic concentrations of sodium alendronate in places of bone resorption of various etiology, in pathologic fractures, and other conditions associated with the need to repair bone tissues.
The essence of the invention, as far as the pharmaceutical composition in gel dosage form for the prevention and treatment of osteoporosis and other conditions associated with the need to repair bone tissue are concerned, is that it includes biphosphonate as an active ingredient, wherein biphosphonate is incorporated into phospholipid vesicles formed from the lipid and hydrophilic phases that include ingredients with the following ratio, mass %:
biphosphonate 0.01-2.0; egg lecithin 1.0-6.0;essential pine oil 0.05-0.2; camphor oil 0.01-1.0; olive oil 0.01-5.0; vitamin E 0.01-0.15;vitamin D 0.01-0.2; carbopol 0.4-0.6;NaOH0.42;glycerin 2.0-4.0;nipagin0.3;nipasol0.1;waterthe rest.
Preferably, biphosphonate is selected from the following group: alendronate, risedronate, etidronate, clodronate, and pamidronate, wherein the dimensions of phospholipid vesicles that include biphosphonate are in a range from 50 nm to 250 nm.
The essence of the invention, as far as the method for the treatment of resorption of bone tissue of various etiology is concerned, is that said pharmaceutical composition in gel dosage form includes biphosphonate as an active ingredient, wherein biphosphonate is incorporated into phospholipid vesicles formed from lipid and hydrophilic phases that include ingredients in the following ratio, mass %; biphosphonate 0.01-2.0; egg lecithin 1.0-6.0; essential pine oil 0.05-0.2; camphor oil 0.01-1.0; olive oil 0.01-5.0; vitamin E 0.01-0.15; vitamin D 0.01-0.2; carbopol 0.4-0.6; NaOH 0.42; glycerin 2.0-4.0; nipagin 0.3; nipasol 0.1; water the rest. Preferably, biphosphonate is selected from the following group: alendronate, risedronate, etidronate, clodronate, pamidronate, wherein the dimensions of the phospholipid vesicles that include biphosphonate are in a range from 50 nm to 250 nm. The gel is applied on the skin at places of diagnosed resorption or destruction of bone tissue.
The essence of the invention, as far as the method for the treatment of osteoporosises in patients with pathology of the gastrointestinal tract organs is concerned, is that said pharmaceutical composition in gel dosage form includes, as an active ingredient, biphosphonate incorporated in phospholipid vesicles formed from lipid and hydrophilic phases that include ingredients with the following ratio, mass %: biphosphonate 0.01-2.0; egg lecithin 1.0-6.0; essential pine oil 0.05-0.2; camphor oil 0.01-1,0; olive oil 0.01-5.0; vitamin E 0.01-0.15; vitamin D 0.01-0.2; Carbopol 0.4-0.6; NaOH 0.42; glycerin 2.0-4.0; Nipagin 0.3; Nipasol 0.1; water the rest. Preferably, biphosphonate is selected from the following group: alendronate, risedronate, etidronate, clodronate, pamidronate, wherein the dimensions of the phospholipid vesicles that include biphosphonate are in a range from 50 nm to 250 nm. Transdermal application of gel in this case excludes GIT blennosis that is typical when taking biphosphonates orally.